| *600016 | |||||||||||||||
| CONTACTIN 1; CNTN1 | |||||||||||||||
| HGNC Approved Gene Symbol: CNTN1 | |||||||||||||||
| Cytogenetic location: 12q12 Genomic coordinates (GRCh37): 12:41,086,357 - 41,464,093 (from NCBI) | |||||||||||||||
| Gene Phenotype Relationships | |||||||||||||||
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| Cloning | |||||||||||||||
| Chick contactin (also known as F11 in the chick and F3 in the mouse) is a neuronal cell adhesion molecule of the immunoglobulin superfamily that is composed of 6 C2 Ig domains and 4 fibronectin type III (FN-III) repeats. In the developing mouse cerebellum, contactin is confined to discrete neuronal subpopulations and subcompartments, for example, the granule cell axons, Golgi cells, and mossy fibers, while in contrast, stellate cells and Purkinje cell bodies and dendrites are devoid of contactin expression. This restricted distribution led to the speculation that contactin is of critical importance in the formation of axon patterns in developing embryos. Berglund and Ranscht (1994) used a biochemical approach to isolate contactin from adult human brain. Biochemical and immunohistochemical characterization of the protein, then called Gp135, revealed that it is a glycosylphosphatidylinositol (GPI)-anchored neuronal membrane protein with amino-terminal and internal peptide sequences closely similar to those of chick contactin/F11 and mouse F3. Berglund and Ranscht (1994) isolated and characterized cDNA clones encoding human contactin. Two putative contactin-1 isoforms were isolated. | |||||||||||||||
| Gene Function | |||||||||||||||
| Using immunoprecipitation and fluorescence microscopy, Hu et al. (2003) identified mouse F3 as a physiologic ligand and activator of Notch (190198). Upon activation by F3, Notch signals through Dtx1 (602582), which leads to oligodendrocyte maturation via upregulation of certain myelin-related proteins. Thus, Hu et al. (2003) concluded that Notch does not solely function to inhibit oligodendrocyte precursor differentiation to mature cells, and they suggested that it may be useful in promoting remyelination in degenerative diseases. Compton et al. (2008) found low levels of CNTN1 expression in normal human and mouse skeletal muscle that was restricted to the neuromuscular junction (NMJ). In patients with secondary dystroglycanopathies, such as Fukuyama muscular dystrophy (253800) and muscle-eye-brain disease (253280), CNTN1 was not restricted to the NMJ, but was also found in the sarcolemmal membrane. In contrast, in either denervated skeletal or skeletal muscle of patients with generalized dystrophic Duchenne muscular dystrophy (310200), sarcolemmal expression of CNTN1 was not observed. These findings suggested that mistargeting of CNTN1 to the sarcolemmal membrane is associated with the loss of glycosylated membrane-bound alpha-dystroglycan (128239), not with primary dystrophic or neuropathic processes. | |||||||||||||||
| Mapping | |||||||||||||||
| By fluorescence in situ hybridization, Berglund and Ranscht (1994) mapped the CNTN1 gene to chromosome 12q11-q12. | |||||||||||||||
| Molecular Genetics | |||||||||||||||
| In affected infants from a consanguineous Egyptian family with Compton-North congenital lethal myopathy (612540), Compton et al. (2008) identified a homozygous mutation in the CNTN1 gene (600016.0001). The phenotype was severe, with fetal akinesia and nonspecific myopathic features on skeletal muscle biopsy. Most notable was the absence of alpha-dystrobrevin (DTNA; 601239) and beta-2-syntrophin (SNTB2; 600027) from the sarcolemma (Jones et al., 2003). Compton et al. (2008) proposed that reduced expression of CNTN1 at the neuromuscular junction causes a defect in neuromuscular transmission, resulting in a severe myopathic phenotype. The loss of DTNA and SNTB2 is likely secondary to defective neuromuscular transmission or signaling. The findings emphasized an overlap in the clinical spectrum of congenital myopathies with fetal akinesia and congenital myasthenic syndromes (see, e.g., 608931), and suggested that proteins related to NMJ adhesion are important for normal muscle development and growth. | |||||||||||||||
| Animal Model | |||||||||||||||
| Berglund et al. (1999) ablated contactin gene expression in mice by targeted disruption. Contactin -/- mutants displayed a severe ataxic phenotype consistent with defects in the cerebellum and survived only until postnatal day 18. At birth, contactin mutants were indistinguishable from wildtype littermates, but by postnatal day 10, the mutants exhibited an overt ataxic phenotype that increased in severity over subsequent days. Defects in controlling voluntary movements, posture, and balance were accompanied by failure to gain body weight and progressive weakening. By postnatal day 15, the homozygous mutants in a litter could be identified by their smaller size, emaciated appearance, and uncontrolled movements. Analysis of the contactin -/- mutant cerebellum revealed defects in granule cell axon guidance and in dendritic projections from granule and Golgi cells. These results demonstrated that contactin controls axonal and dendritic interactions of cerebellar interneurons and contributes to cerebellar microorganization. Compton et al. (2008) found that Cntn1-null mice retained staining for alpha-dystrobrevin and beta-2-syntrophin at the skeletal muscle sarcolemma, which was in contrast to humans with mutations in the CNTN1 gene who have secondary loss of these proteins at the sarcolemma. | |||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | |||||||||||||||
| Table View | |||||||||||||||
| .0001 MYOPATHY, CONGENITAL, COMPTON-NORTH | |||||||||||||||
| CNTN1, 1-BP DUP, 871T | |||||||||||||||
| In 4 affected infants with lethal infantile congenital myopathy (612540), from a large consanguineous kindred of Egyptian origin, Compton et al. (2008) identified a homozygous 1-bp duplication (871dupT) in exon 8 of the CNTN1 gene, resulting in a frameshift and premature truncation within the third Ig domain. The mutation was predicted to result in nonsense-mediated mRNA decay. The mutation was not present in 121 healthy controls of mixed ethnicity or in 27 unrelated myopathy patients. | |||||||||||||||
| REFERENCES | |||||||||||||||
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